The present invention is directed to a method for making compositions and compounds useful for modulating animal brain excitability via the gamma-aminobutyric acid (GABA) receptor-chloride ionophore complex (GR complex).
A variety of steroid derivatives, such as 3.alpha.-hydroxy,3.beta.-methyl-5.alpha.-pregnan-20-one, have been shown to be effective in stimulating the GR complex, with a variety of physiological effects. See U.S. Ser. No. 07/745,216, 07/521,724, and 07/379,047, incorporated herein by reference. The standard procedure for making this compound and other 3.alpha.-hydroxy,3.beta.-substituted-pregnanes includes a step wherein compounds with two keto groups have one group protected prior to reaction at the other keto group to produce a 3.beta.-substituted pregnane. During this process, one method of protecting the 20-keto group is to change it to an ethylene ketal group. See U.S. Pat. No. 3,953,429. The drawbacks of this method include the requirement for the use of two steps--protection before reaction at the 3-keto position and deprotection after reaction--with their accompanying loss in material.
We have discovered a novel method for production of 3.alpha.-hydroxy, 3.beta.-substituted-pregnanes which does not require protection of the 20-one group. By this method, each ketone group is treated independently. A variety of groups can be substituted into the 3.beta. position. The ketone at the 20 position can also be modified in an independent manner.